Cytarabine - instructions for use, dose, side effects, contraindications

Active substanceCytarabineCytarabine

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Dosage form: & nbsplyophilizate for solution for injection

Composition:

1 ampoule contains:

active substance: cytarabine (in terms of 100% substance) 100 mg;

auxiliary substance: povidone low molecular weight 5 mg.

Description:

A porous mass of white colored, compacted into a tablet.

Pharmacotherapeutic group:antitumour agent - antimetabolite

ATX: & nbsp

L.01.B.C.01 Cytarabine

Pharmacodynamics:

Cytarabine belongs to the group of pyrimidine antimetabolites exchange and is an S-phase-specific drug. Inhibits synthesis of deoxyribonucleic acid (DNA) in a tumor (leukemic) cell. The drug acquires anti-leukemia as a result of phosphorylation in arabinosyl cytosine triphosphate (Ara-CTF), which competitively inhibits DNA polymerase. In addition, there is evidence that DNA synthesis is also inhibited by the incorporation of cytarabine into DNA and ribonucleic acids (RNA).Has immunosuppressive properties.

Several mechanisms of development of resistance to cytarabine are known: inhibition of membrane transport, deficiency of phosphorylating enzymes, increased activity of inactivating enzymes, decreased affinity of DNA polymerase or increased pool of deoxy-CTF. Cytotoxic effect is achieved when creating permanent, high intracellular concentrations of Ara-CTF.

Pharmacokinetics:

After intravenous administration cytarabine quickly and almost completely turns into inactive uracil metabolite (Ara-U) for the action of cytidine deaminase in the liver and other tissues. The half-life in the initial phase is 10 minutes, in the final half-about 1-3 hours. Since the activity of deaminase in the central nervous system (CNS) is minimal, excretion of cytarabine from the cerebrospinal fluid occurs slowly, and the period of its half-elimination is 2-11 hours. With continuous intravenous infusions cytarabine in usual doses (100-200 mg / m² surface of the body) are reached concentrations equal to 0.04-0.6 μmol / l. With subcutaneous (SC) administration, the maximum concentration in the plasma is reached within 20-60 minutes.Then a two-phase decrease in concentration occurs.

An insignificant part of cytarabine undergoes phosphorylation by kinases at the intracellular level, resulting in the formation of an active metabolite Ara-CTP.

The connection with plasma proteins is 15%. Cytarabine penetrates the blood-brain barrier. After a continuous infusion into the cerebrospinal fluid, a concentration equal to 10-40% of the plasma concentration is achieved. After the administration of usual or high doses, only 4-10% of the administered dose is excreted by the kidneys unchanged. In the first 24 hours 71-96% of the injected drug is found in urine in the form of Ara-U.

Indications:

- Acute non-lymphoblastic or acute lymphoblastic leukemia in children and adults (for induction of remission, and maintenance therapy alone or as part of combination therapy);

- chronic myeloid leukemia (blast crisis);

- non-Hodgkin's lymphoma in children and adults (as part of combination therapy);

- Acute neuroleukemia in children and adults (intrathecal application);

High-dose cytarabine therapy:

- non-Hodgkin's lymphomas refractory to therapy;

- refractory to therapy acute non-lymphoblastic and / or lymphoblastic leukemia, as well as variants with unfavorable prognosis;

- recurrence of acute leukemia;

- secondary leukemia after previous chemotherapy and / or radiation therapy;

- manifest leukemia after the transformation of the preleukosis;

- Acute non-lymphoblastic leukemia in patients younger than 60 years of age (for consolidation of remission);

Blast crises in chronic myelogenous leukemia.

Contraindications:

- Hypersensitivity to cytarabine and other components of the drug;

- Pregnancy and the period of breastfeeding.

Carefully:

Inhibition of bone marrow hemopoiesis, bone marrow infiltration by tumor cells, acute viral infectious diseases (including chicken pox, shingles), fungal or bacterial nature (risk of serious complications and generalization of the process), hepatic and / or renal failure, radiation or chemotherapy ( including in history), diseases in which there is an increased risk of hyperuricemia (gout or urate nephrolithiasis). Age over 60 years (with the appointment of high-dose therapy).

Dosing and Administration:

Intravenously sprayed or infusion, subcutaneously or intrathecally. It is used either in the form of monotherapy in usual doses, as part of chemotherapy programs with high doses, or as part of combined chemotherapy.The dose, duration, and frequency of the assignment depend on the chosen program.

Immediately before consumption cytarabine is dissolved in isotonic (0.9%) sodium chloride solution or in water for injection (calculated: intravenous - 100 mg of cytarabine in 400 ml of solvent; for subcutaneous and intrathecal administration - 100 mg of cytarabine in 1 ml of solvent).

The average daily dose is 100-200 mg / m². Elderly patients or with reduced hematopoiesis reserves - 50-70 mg / m².

Induction of remission in acute leukemia: in combination with other antitumor drugs - 100 mg / m²/ day as a continuous intravenous infusion for 7 days or 100 mg / m² in / in every 12 hours for 7 consecutive days. In total, 4-7 treatment courses are conducted. Intervals between courses - not less than 14 days.

The maintenance dose is subcutaneous, 1-1.5 mg / kg 1 or 2 times a week.

High-dose therapy. Patients with resistant to cytarabine acute leukemia or lymphoma is possible to assign the drug at high doses - intravenous drip, for 1-3 hours, 2-3 g / m² 2 times a day (every 12 hours) for 2-6 days.

Intrathecal Therapy. At neiroleukoze to adults - from 5 to 75 mg / m² from 1 time per day, for 4 days to 1 time in 4 days,depending on the type and severity of neurologic symptoms and the effectiveness of previous therapy. The commonly used dose for adults and children is 30 mg / m² every 4 days before the normalization of cerebrospinal fluid, followed by the introduction of another additional dose.

Side effects:

By frequency, the side effects were divided into the following categories: very frequent 1/10; Frequent 1/100 and <1/10; infrequent 1/1000 and <1/100; rare 1/10 000 and <1/1000; very rare <1/10 000.

Allergic reactions: often - itching, hives; infrequent - rash, fever; rarely - anaphylactoid reactions, allergic edema; very rarely skin desquamation.

From the central nervous system: often - with the appointment of high doses: paresthesia of the toes and facial skin, impaired cerebellum function (speech disorder, ataxia, tremor); infrequently - a violation of the central nervous system (dizziness, headache, impaired consciousness, weakness, drowsiness, memory impairment, convulsions, coma), peripheral sensorimotor neuropathy, neuritis, late progressive ascending paralysis.

From the skin: often - reversible skin disorders, integument, skin pigmentation, alopecia,bullous dermatitis, vasculitis, infrequent - ulceration, itching, burning pain in the palms and soles, cellulitis at the injection site, the appearance of freckles; very rarely - neutrophilic endocrine tuberous abscess, erythroderma.

From the muscular system: infrequently - myalgia, arthralgia.

From the urinary system: infrequent urine retention, hyperuricemia, urate nephropathy (as a result of rapid cell destruction).

From the digestive system: often - difficulty swallowing, decreased appetite, nausea, vomiting, abdominal pain, diarrhea, anorexia, inflammation or ulceration of the oral mucosa or anal area; infrequently - esophagitis, ulceration of the esophagus, cystic pneumatosis of the intestine, leading to peritonitis, necrotic colitis, impaired liver function of varying severity, hyperbilirubinemia, jaundice; rarely bleeding, liver abscess, necrosis of the small intestine, peritonitis, acute pancreatitis (especially after the previous appointment of L-asparaginase).

On the part of the organs of hematopoiesis: often - anemia, megaloblasticosis, leukopenia, thrombocytopenia; rarely - reticulocytopenia; infrequently - sepsis (immunosuppression).

On the part of the respiratory system: infrequently - pneumonia, diffuse interstitial pneumonitis, pain in the chest; rarely - pulmonary edema, a feeling of lack of air, an acute respiratory distress syndrome.

From the sense organs: often - reversible hemorrhagic conjunctivitis (photophobia, burning, visual impairment, lacrimation), keratitis, including ulcerative - with high-dosage therapy.

From the side of the cardiovascular system: very often - arrhythmia; infrequently - pericarditis, cardiomyopathy.

Local Reactions: often - burning at the injection site; infrequently - phlegmon and thrombophlebitis.

Cytarabine Syndrome (febrile syndrome, myalgia, ossalgia, pain in a difficult cage, maculopapular rash, conjunctivitis), infections, inadequate secretion of antidiuretic hormone (ADH), thrombosis of hepatic veins, rhabdomyolysis.

After intrathecal administration: paraplegia, leukoencephalopathy, neurotoxic effect, loss of vision.

Overdose:

Intravenous drip introduction 4.5 g / m² every 12 hours for 12 days leads to irreversible CNS damage incompatible with life.

Symptoms: with a chronic overdose, massive bleeding is possible due to severesuppression of the bone marrow, the development of life-threatening infections, the manifestation of neurotoxicity.

Treatment: symptomatic, there is no specific antidote.

Interaction:

With simultaneous use with digoxin, a decrease in the equilibrium concentration (C_ss) digoxin and its excretion by the kidneys (careful digoxin content control is required). C_ss digitoxin does not change.

When combined with other antitumor drugs, radiation therapy may enhance mutual toxicity and immunosuppressive effects.

Immunosuppressants (azathioprine, chlorambucol, glucocorticosteroids, cyclophosphamide, ciclosporin, mercaptopurine, tacrolimus) increase the risk of developing infectious complications.

Ineffective vaccination with vaccines with killed viruses (due to a decrease in protective mechanisms, the formation of antibodies is reduced) and with living viruses (an increase in side effects, a decrease in the formation of antibodies).

Conducted in vitro studies of the interaction between gentamicin and cytarabine revealed antagonism, which may reduce the sensitivity of strains Klebsiella pneumonia to gentamicin.

Pharmaceutically incompatible with heparin, insulin, methotrexate, fluorouracil, naftticillin, oxacillin, benzylpenicillin, methylprednisolone.

Chemically stable in a 5% solution of dextrose, 0.2-0.9% solution of sodium chloride in an amount of 2.6 and 8 grams per 250 ml. In concentrations of 2 mg / ml it is stable in the presence of potassium chloride (50 meq / 500 ml), in a 0.9% solution of sodium chloride or in a 5% solution of dextrose. At concentrations of 1 mg / ml and 0.2 mg / ml, it is stable in a solution of sodium bicarbonate (50 meq / L), in a 5% solution of dextrose or 0.24% solution of sodium chloride.

Special instructions:

Treatment with cytarabine is controlled by the number of leukocytes in the peripheral blood (daily or every other day) and bone marrow (before and after each course of therapy).

With a platelet count of less than 50000 / mm³ and / or polymorphonuclear granulocytes below 1000 / mm³ treatment is stopped.

In all patients receiving cytarabine, periodic monitoring of liver and kidney function is necessary.

It is necessary at least once a week to monitor the functional state of the liver, before and after the end of the course of cytarabine therapy, to monitor the excretory function of the kidneys.

When carrying out programs of high-dosage therapy with cytarabine, daily monitoring of the general blood test and biochemical indices is necessary. Patients with initial hyperleukocytosis or a large tumor mass (with lymphomas) need control of the level of uric acid in the blood.

For the prevention of hyperuricemia, the appointment of allopurinol and the intake of a sufficient amount of fluid is recommended.

In experimental studies, teratogenic, embryotoxic and mutagenic effects of cytarabine have been established.

After 24 hours after administration, the number of leukocytes decreases, reaches 7-9 days minimum values, then briefly increases to 12 days, then again decreases with a minimum of 15-24 days. In the next 10 days the number of leukocytes increases rapidly to the initial level. The number of platelets is significantly reduced on the 5th day after cytarabine administration, the lowest level is reached on days 12-15, the baseline level is reached during the next 10 days.

Control of the bone marrow pattern continues after the disappearance of blast cells from peripheral blood. The number of elements in the peripheral blood can continue to decrease after the drug is withdrawn and reach the minimum values after 12-24 days.Therapy is resumed in cases of clear signs of bone marrow restoration and the presence of indications, without waiting for the normalization of peripheral blood.

In order to reduce the nausea and vomiting that occur against the background of rapid intravenous administration of large doses of the drug and continuing for several hours after the injection, it is recommended to administer the drug by prolonged infusions. When carrying out high-dosage therapy, do not recommend using a solvent containing gasoline alcohol. In case of accidental contact with the skin, wash it with running water and soap.

Effect on the ability to drive transp. cf. and fur:

During treatment, you should not drive vehicles and engage in potentially dangerous activities that require increased attention and speed of psychomotor reactions.

Form release / dosage:Lyophilizate for solution for injection, 100 mg.

Packaging:

For 100 mg of cytarabine in ampoules of colorless glass.

5 ampoules, together with the instruction for use and the ampoule scarifier, are placed in a pack of cardboard.

When using ampoules with a break ring, it is allowed to pack the ampoules without an ampoule scarifier.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-001429

Date of registration:07.07.2011

The owner of the registration certificate:BELMEDPREPARATY, RUP BELMEDPREPARATY, RUP Republic of Belarus

Manufacturer: & nbsp

BELMEDPREPARATY, RUP Republic of Belarus

Representation: & nbsp"Belmedpreparaty" RUP "Belmedpreparaty" RUP

Information update date: & nbsp29.09.2015

Illustrated instructions

Instructions

Cytarabine (Cytarabine)